Is HAL p.Arg208Gln (c.623G>A) pathogenic?

HAL p.Arg208Gln (c.623G>A) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4227); Very rare (popmax 0.00534%, afr); Associated with histidinemia.

What condition is associated with HAL p.Arg208Gln (c.623G>A)?

HAL p.Arg208Gln (c.623G>A) is associated with histidinemia (ClinVar).

How common is HAL p.Arg208Gln (c.623G>A) in the general population?

HAL p.Arg208Gln (c.623G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Histidinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HAL p.Arg208Gln (c.623G>A)?

AlphaMissense predicts ambiguous (score 0.4227) — an in-silico prediction, not a clinical call.

HAL p.Arg208Gln

c.623G>A · rs121434328 · VCV881468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4227 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.4227	ambiguous
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -8.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.32	acceptor loss · deltas
Pangolin	Δ0.31	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,876 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00186% 30/1,612,620 alleles · very rare exomes 24/1,460,460 · genomes 6/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,719
Remaining individualsnot grpmax-eligible	0.0048%	20,815
East Asian	0.00446%	22,436
European (non-Finnish)	0.00178%	56,133

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HAL
Protein: p.Arg208Gln
Coding: c.623G>A
MANE Select: NM_002108
dbSNP: rs121434328
Type: single nucleotide variant
Location: chr12:95992772 (GRCh38)
Gene constraint: LOEUF 1.213 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 208: a UniProt-annotated variant site (in histid)

Full HAL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

histidinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Histidinemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

HAL p.Arg208Trp Uncertain significance ★ ⚠ same residue
HAL c.*392C>T Uncertain significance ★★ same condition
HAL p.Arg9Cys Uncertain significance ★★ ⚠ same condition
HAL p.Asn476Lys Uncertain significance ★★ ⚠ same condition
HAL p.Glu472Lys Uncertain significance ★★ ⚠ same condition
HAL p.Gly165Ser Uncertain significance ★★ ⚠ same condition
HAL p.Leu242Met Uncertain significance ★★ ⚠ same condition
HAL p.Phe485Leu Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hal-p-arg208gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown